Background: Evidence suggests that major depressive disorder is related to neuroaxonal injury and that neuroflament light chain (NfL) is a biomarker of neuroaxonal injury. In addition, proinflammatory cytokines have been reported to be associated with major depression and neuroaxonal injury. Methods: Forty patients with major depression and 40 age- and sex-matched healthy control participants were enrolled for the measurement of NfL and proinflammatory cytokines and assessment of executive function. General linear models were used to examine the association between NfL levels, proinflammatory cytokine levels, and executive function. Results: Patients with major depressive disorder exhibited significantly higher NfL levels (P = .007) than the control participants. NfL levels were positively related to log-transformed levels of tumor necrosis factor-alpha (P = .004). Higher levels of NfL (P = .002) and tumor necrosis factor-alpha (P = .013) were associated with greater deficits in executive function. Discussion: NfL was a novel biomarker for major depressive disorder and related executive dysfunction. Further studies are necessary to elucidate the role of NfL in the pathophysiology of major depression and related cognitive impairment. Keywords: Cognitive function, major depressive disorder, neuroflament light chain, proinflammatory cytokines